Abstract
Formaldehyde (FA) is a common air pollutant. Exposure to exogenous FA can cause damage to the nervous system, such as learning and memory impairment, balance dysfunction, and sleep disorders. Excessive production of endogenous FA also causes memory impairment and is thought to be associated with Alzheimer’s disease (AD). Tumor necrosis factor alpha-induced protein 1 (TNFAIP1) plays a crucial role in neurodevelopment and neurological diseases. However, the role of TNFAIP1 in FA-induced neurotoxicity is unclear. Herein, using a mouse neuroblastoma cell line (N2a cells), we explored the mechanism of TNFAIP1 in FA-induced neurotoxicity, the involvement of the Akt/CREB signaling pathway, and how the expression of TNFAIP1 is regulated by FA. We found that exposure to 100 μM or 200 μM FA for 24 h led to decreased cell viability, increased cell apoptosis and neurite retraction, increased reactive oxygen species (ROS) levels, upregulated protein expression of TNFAIP1 and decreased the levels of phosphorylated Akt and CREB in the Akt/CREB pathway. Knockdown of TNFAIP1 using a TNFAIP1 small interfering RNA (siRNA) expression vector prevented FA from inhibiting the Akt/CREB pathway, thus reducing cell apoptosis and restoring cell viability and neurite outgrowth. Clearance of ROS by vitamin E (Vit E) repressed the FA-mediated upregulation of TNFAIP1 expression. These results suggest that FA increases the expression of TNFAIP1 by inducing oxidative stress and that upregulated TNFAIP1 then inhibits the Akt/CREB pathway, consequently leading to cell apoptosis and neurite retraction. Therefore, TNFAIP1 is a potential target for alleviating FA-induced neurotoxicity and related neurological disorders.
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Funding
This study was supported by National Natural Science Foundation of China (21806036, 81972642, 81770389), Hunan Provincial Natural Science Foundation of China (2018JJ3330), the Doctoral Scientific Research Startup Foundation and Youth Science Foundation of Hunan Normal University (31401), and the Cooperative Innovation Center of Engineering and New Products for Developmental Biology of Hunan Province (20134486).
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Yi, J., Zhu, M., Qiu, F. et al. TNFAIP1 Mediates Formaldehyde-Induced Neurotoxicity by Inhibiting the Akt/CREB Pathway in N2a Cells. Neurotox Res 38, 184–198 (2020). https://doi.org/10.1007/s12640-020-00199-9
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DOI: https://doi.org/10.1007/s12640-020-00199-9